Modern medicine has provided various techniques and methods for treating cancer patients. However, before any of such techniques or methods can be used for treatment of cancer patients, it is first necessary to detect the cancer in the patient. Experience has shown that the earlier the cancer is detected the greater the likelihood that the cancer can be effectively treated (e.g., by surgery, chemotherapy, or other known procedures).
An increased incidence of vascular thrombosis and disseminated intravascular coagulation associated with malignant disease has been known for a long time. It has also been known that there is increased removal of fibrinogen from the circulation of experimental animals and humans with cancer, and much of this fibrin is deposited in and around the solid tumor.
Fibrin deposition is thought to promote tumor growth by providing a supporting network or "cocoon" of fibrin in which new cells can grow. Alternatively, it may protect the malignant cells from the host defense system. Fibrin is associated with blood-borne malignant cells that are potentially metastatic. This fibrin may facilitate clumping of tumor cells with other blood cells such that the tumor cell embolus will lodge in small capillaries of organs susceptible for tumor growth (e.g., the lung).
The administration of anticoagulants and fibrinolytic agents to experimental animals decreases tumor growth and metastasis. It has also been demonstrated that malignant tissue has increased procoagulant and fibrinolytic activity.
Cancer procoagulant has been purified and characterized from malignant tissue. It is not present in normally differential cells and tissue. See, for example, Isolation and Characterization of Cancer Procoagulant: A Cysteine Proteinase From Malignant Tissue, Biochemistry, 24, 5558 (1985); A Factor X-Activating Cysteine Protease From Malignant Tissue, J. Clin. Invest., Volume 56, pp. 1665-1671 (June, 1981); and Comparison of Procoagulant Activities In Extracts of Normal and Malignant Human Tissue, J. Nat'l. Cancer Inst., Vol. 62, No. 4 (April, 1979); each of which is incorporated herein by reference. See also my U.S. Pat. No. 4,461,833 which describes techniques for purifying cancer procoagulant from animal tissue extract, incorporated herein by reference.
Cancer procoagulant is a cysteine proteinase with a molecular weight of 68,000 that initiates coagulation by directly activating factor X in the coagulation cascade. It is physically, chemically and enzymatically distinct from other coagulation enzymes. In particular, it is distinct from tissue factor. Tissue factor is a membrane lipoprotein that initiates coagulation via factor VII and is present in both normal and malignant cells.
The activation of factor X by cancer procoagulant can be more easily understood with reference to FIG. 1, which is a schematic diagram showing the activation of both the intrinsic and extrinsic pathways. Activation of the intrinsic pathway by surface contact causes factor XII to form factor XIIa, which, acting through the proteolytic conversions of factors XI and IX, results in an active complex composed of factor IXa, factor VIII, calcium and phospholipid, all of which facilitates the proteolytic activation of factor X to Xa. Tissue damage facilitates the exposure of tissue factor which, when it binds to factor VIIA, forms a very potent activator of factor X. Cancer procoagulant is a cysteine proteinase that directly activates factor X. Russell's Viper Venom (R.V.V.) is a serine proteinase that directly activates factor X and has been used herein as a control activator of the assay. The conversion of factor X, in turn, by either intrinsic or extrinsic pathways, activates prothrombin (II) to thrombin (IIa) in the presence of calcium, phospholipid, and factor V. Thrombin converts fibrinogen to fibrin and activates factor XIII which facilitates fibrin monomer polymerization.
There has not heretofore been provided a method or technique for detecting the presence of cancer procoagulant activity in blood serum.